Project Summary/Abstract Severe/exacerbation-prone asthma remains a major problem with significant morbidity and mortality despite the development of new targeted therapies. The goal of the NHLBI?s Precision Interventions for Severe and Exacerbation Prone Asthma (PrecISE) Network is to conduct sequential, adaptive, clinical trials with precision interventions in stratified patient populations, utilizing patient phenotypes/endotypes. We hypothesize that a biomarker-directed approach, applied in an adaptive trial, can be used to define phenotypic/endotypic features of severe/exacerbation-prone asthma, predict response to specific precision interventions, and be useful in selecting one precision intervention therapy over another. We thus propose the following Specific Aims: 1. Conduct a sequential, adaptive clinical trial with the PrecISE Network for adults and adolescents with severe/exacerbation-prone asthma, utilizing currently available patient phenotypes/endotypes, and monitoring biomarkers to validate their utility in predicting response to precision intervention strategies including anti-IL5, anti-IL4/13, anti-IgE, and anti IL6. 2. Demonstrate that a biomarker-driven strategy utilizing blood eosinophils, exhaled nitric oxide and plasma IL6 or CRP levels, applied in a hierarchical manner with an adaptive design, can be used to select the best precision intervention for a patient with a specific phenotype/endotype. 3. Evaluate next generation biomarkers (including cytokine profiling, RNA seq, pathway analysis, and expression of steroid response genes in blood, sputum and/or nasal brushings) as predictors of response to specific asthma interventions. We propose an 800-subject clinical trial that uses a sequential, adaptive trial design model to select precision interventions, including anti-IL5, anti-IL4/13, anti-IgE and anti-IL6, in severe/exacerbation-prone asthma patients with specific endotypes. We will explore current biomarkers (including blood eosinophils, exhaled nitric oxide, serum IL-6, CRP), applied in a hierarchical approach, as well as next generation biomarkers. We will determine whether a change in a designated biomarker will be associated with a response to the precision intervention therapy. For those who fail to respond to our interventions, we will obtain chest/sinus CT scans and bronchoscopy with biopsy and lavage to define tissue-specific strategies for precision interventions. We will leverage the experience and established clinical trial program of the Denver site with expertise in phenotyping/endotyping, biomarker development, and analytic approach, to meet our ultimate goals of using adaptive trial design as a model for clinical care, to fill the gap in managing severe/exacerbation-prone asthma and defining a new generation of biomarkers based on assessment of individual treatment response and failure within the study population.